Cancer Risk

Frameshift deletion in the CHEK2 checkpoint kinase that abolishes kinase activity, conferring moderate-penetrance susceptibility to breast, colorectal, and prostate cancer

Second most common pathogenic MUTYH variant; biallelic carriers develop MUTYH-Associated Polyposis with ~10-fold increased colorectal cancer risk, while heterozygous carriers have modestly elevated CRC risk (OR ~1.2-1.5)

Most common pathogenic MUTYH variant; biallelic carriers develop MUTYH-Associated Polyposis with ~28-fold increased colorectal cancer risk, while heterozygous carriers have a modest CRC risk elevation (OR ~1.3)

Intergenic enhancer variant near MYC oncogene — modestly increases colorectal and prostate cancer susceptibility via Wnt signaling

Missense variant in the APC tumor suppressor that creates a hypermutable poly-A tract, increasing somatic mutation rate and colorectal cancer risk approximately 1.5-2 fold — strongly enriched in Ashkenazi Jewish populations (~6% carrier frequency)

Missense variant in the XPD helicase that reduces nucleotide excision repair fidelity, modestly increasing susceptibility to UV-induced and carcinogen-induced DNA damage across multiple cancer types

Base excision repair scaffold protein that coordinates repair of oxidative DNA damage and single-strand breaks; the Gln variant reduces repair efficiency at the PARP-binding domain

Missense variant in the linker region of XRCC1 that disrupts interaction with the OGG1 glycosylase, impairing base excision repair of oxidative DNA damage; effect direction varies by cancer type and ancestry

Moderate-penetrance stop-gain variant truncating the last 93 amino acids of BRCA2, associated with modestly increased risk of breast, ovarian, and lung cancers — distinct from pathogenic BRCA2 mutations

Component of the MRN complex essential for DNA double-strand break repair, telomere maintenance, and cell cycle checkpoint signaling; this variant alters the BRCT domain and modestly impairs DNA damage response

Regulatory variant in the MDM2 promoter that increases Sp1 transcription factor binding, raising MDM2 levels and accelerating p53 degradation — associated with earlier age of cancer onset

Promoter variant in the MLH1 DNA mismatch repair gene that reduces transcriptional activity and predisposes to promoter hypermethylation, increasing colorectal cancer risk through microsatellite instability

Common missense variant in BRCA1 with debated association to modest breast cancer risk — NOT a pathogenic BRCA1 mutation

Common missense variant near the BRCA1 RING finger domain; associated with modestly elevated breast cancer risk (OR ~1.1-1.3) but classified as benign/likely benign — not a pathogenic BRCA1 mutation

Synonymous variant in CYP1A2 exon 7 in linkage disequilibrium with the *1F high-inducibility haplotype; carriers activate more heterocyclic amines and PAHs from cooked meat and smoke into DNA-damaging intermediates

Regulatory variant near FOXE1 at 14q13.3 that reduces PTCSC3 tumor suppressor expression, increasing risk of papillary thyroid cancer

Functional 5' UTR variant in the FOXE1 thyroid transcription factor that increases papillary thyroid cancer risk by recruiting USF1/USF2 transcription factors to upregulate FOXE1 expression

5' UTR variant in the XPA DNA damage recognition gene that modulates nucleotide excision repair capacity, influencing cancer susceptibility and platinum-based chemotherapy response